The long-term goal of this research is to develop drugs that are safe and effective against drug-resistant malaria. Malaria is one of the most common infectious diseases in the world. It affects approximately 300 million people and leads to more than 2 million death a year. The increasing prevalence of multiple drug resistant strains of Plasmodium falciparum in most malaria endemic areas has significantly reduced the efficacy of current antimalarial drugs for both treatment and prophylaxis and there is a clear need for new medicinal agents based on novel mode of action. Febrifugine is an alkaloid isolated from roots of Dichroa febrifuga Lour and showed powerful antimalarial activity against P. falciparum. Strong liver toxicity has precluded its clinical use against malaria. In this Phase I study, a focused library of thirty novel febrifugine analogues will be synthesized. They are expected to retain the potent antimalarial activity and desirable ADME (adsorption, distribution, metabolism, and excretion) properties. Lower liver toxicity will be achieved by reducing the tendency to form chemically reactive and toxic intermediates and metabolites. For efficacy evaluation, synthesized compounds will be tested in vitro against two P. falciparum malaria parasite clones: W2 (susceptible to mefloquine but resistant to chloroquine, sulfadoxine, pyrimethamine, and quinine) and D6 (resistant to mefloquine but susceptible to chloroquine, sulfadoxine, pyrimethamine and quinine). For toxicological studies, these compounds will be tested in human adult liver epithelial cells and mouse mammary tumor cells. The specific aim would be the discovery of some less toxic yet still potent compounds whose selectivity (defined as toxicity/anti-malarial activity) equals or greater than 1000. In Phase II study, compounds with desirable selectivity will be synthesized in a large scale and pre-clinical trials will begin by testing these compounds in rodent and primate models to obtain efficacy, ADME and toxicity data. An investigational new drug (IND) application will then be filed with FDA. [unreadable] [unreadable]